CN1981755A - Preparation with solid lipid nano-particle as podophyllotoxin and its derivative carrier - Google Patents

Abstract

The invention provides the application of solid lipid nanoparticles as drug carrier materials for podophyllotoxin and its derivatives. On the other hand, a pharmaceutical composition is also provided, which contains the pharmaceutical active ingredient podophyllotoxin and its derivatives and solid lipid nanoparticles as the drug carrier material. The mass ratio of solid lipid nanoparticles to podophyllotoxin and its derivatives is 15-50. As a drug-loading system for podophyllotoxin and its derivatives, solid lipid nanoparticles have good stability, high encapsulation efficiency, and good release curves, providing an ideal drug-loading system for podophyllotoxin and its derivatives. Way. The above-mentioned pharmaceutical composition has the characteristics of simple preparation process, low cost, and easy control of process parameters; and has the advantages of good biocompatibility, easy biodegradation, film-forming property, flexibility, etc., and has certain anti-inflammatory and antibacterial effects. Improve the efficacy of podophyllotoxin and its derivatives.

Description

Solid Lipid Nanoparticles as New Dosage Forms as Carriers of Podophyllotoxin and Its Derivatives

technical field

The invention relates to the application of solid lipid nanoparticle as a carrier of podophyllotoxin and its derivatives and its new dosage form.

Background technique

Solid lipid nanoparticles (SLN) is a new type of lipid drug-carrying system being developed in the past ten years. It is based on natural or synthetic high-melting solid lipids (such as saturated fatty acid glycerides) , stearic acid, mixed lipid) as the carrier, the nano drug delivery system made by adsorbing or encapsulating the drug in the lipid core. Similar to emulsions and liposomes, SLN uses lipid materials with low toxicity and good biocompatibility as carriers. At the same time, the solid lipid makes it have the advantages of polymer nanoparticles (PNP), such as controlled release of drugs, avoiding degradation or leakage of drugs, and good targeting. SLN's water dispersion system can be sterilized by autoclaving or γ-irradiation, and has long-term physical and chemical stability. It can also be made into solid powder by freeze-drying or spray-drying, and it can also be mass-produced by high-pressure homogenization.

The main components of solid lipid nanoparticles are: (1) lipids, such as fatty acid glycerides (comprising tristearin, tripalmitin, trimyristin, trilaurin, Glyceryl tristearate, Witepsol W 35, Witepsol H35, Witepsol H42, glyceryl monostearate) and fatty acids (such as stearic acid, palmitic acid), etc.; (2) emulsifiers and co-emulsifiers, such as phospholipids ( Including soybean lecithin, egg yolk lecithin and phosphatidylcholine, etc.), Poloxamer, polysorbate, cholate, tyloxapol, etc.; (3) drugs, lipophilic drugs and hydrophilic drugs after esterification can A stable SLN system was prepared with high drug loading and encapsulation efficiency.

Solid lipid nanoparticles are suitable as a slow-release drug delivery system. More importantly, the drug release curve can be modified by changing the lipid skeleton structure, surfactant concentration and production process parameters. The in vitro release of the drug can reach 5 At ~7 weeks, the release profile can be adjusted to either a delayed release with no burst at all, or a partial burst followed by a delayed release, in which cases the burst drug can be given as the first dose.

The distribution of drugs in SLN is mainly determined by drug properties (melting point, polarity, etc.), lipid material properties, surfactant concentration, and process parameters (preparation temperature, etc.), and there are three distribution modes:

1. The drug is uniformly dispersed in the polymer material in molecular form;

2. The drug is adsorbed on the particle surface;

3. The drug is concentrated in the inner core.

If the melting point of the drug is higher than the melting point of the lipid material, the drug will preferentially solidify to form a drug core during cooling, showing sustained release behavior and high encapsulation efficiency; if the melting point of the drug is lower than the lipid material, the lipid will preferentially recrystallize to form a lipid core, The drug is distributed in its outer layer, showing burst release behavior and low encapsulation efficiency. The stronger the lipophilicity of the drug, the more the drug is distributed in the lipid core, the greater the polarity of the molecule, and the lower the encapsulation efficiency.

The route of administration of solid lipid nanoparticles is relatively extensive, and it is a promising new drug delivery system, mainly including the following methods: (1) Injection: SLN was originally a targeted and controlled release drug for intravenous injection. drug design. After the lipid droplets are transformed into solid (SLN), the diffusion coefficient of the drug is reduced, which can slow down the release of the drug. (2) Oral administration: oral dosage forms of SLN include aqueous dispersions and traditional dosage forms containing SLN, such as tablets, pills or capsules. By optimizing the types and doses of emulsifiers and lipids, SLNs that are stable in the gastrointestinal tract can be obtained, and the bioavailability of drugs can be improved and irregular absorption can be reduced by using the adhesion of nanoparticles. SLNs can replace excipients to improve drug distribution in the gastrointestinal tract and control drug release from lipid matrices. (3) Topical administration: Among the solid lipid nanoparticles that have the potential to be put into the market soon, they are used locally. Similar to liposomes, SLNs consist of well-tolerated excipients that, due to their small particle size, possess similar adhesive properties to form a film on the skin. Another significant advantage of SLN is that it is a solid state, which protects the drug from chemical degradation and can also regulate the release of the drug. A very promising application field is to use SLN in sunscreen creams. SLN itself also has a shading effect, which can block ultraviolet rays. The synergistic effect of molecular sunscreens and SLN has opened up a way for the research of a new class of sunscreen creams. (4) Pulmonary drug delivery: The advantage of lipid nanoparticles is that it can control the release of drugs in the lungs and prolong the release time of drugs in the lungs. Lipid nanoparticles degrade faster than polymer nanoparticles. In addition, lipid nanoparticles are well tolerated in vivo and are suitable for loading drugs targeting lung macrophages. Particles in the lungs are susceptible to phagocytosis by macrophages, so lipid nanoparticles can be used to treat infections of the RES system.

Solid lipid nanoparticles use lipid materials with low toxicity and good biocompatibility as carriers. Compared with polymer nanoparticles, the toxicity of SLN is greatly reduced. Using the survival of HL60 cells and human granulocytes as indicators to investigate the in vitro cytotoxicity of different nano-drug delivery systems, it was found that the toxicity of SLN was 90% lower than that of PLGA nanoparticles and 99% lower than that of PBCA nanoparticles. PLA nanoparticles, PLGA nanoparticles and SLN reduce the survival rate of human granulocytes by 50% at a concentration of 0.30%, 0.15%, and greater than 10%, respectively, which shows that SLN has the lowest toxicity and is more suitable as an intravenous drug delivery system Carrier.

Podophyllotoxin is the main active ingredient of podophyllum plants, which are a class of medicinal plants with biological activity and a long history of application. As early as 2,000 years ago, ancient China used the extract of podophyllum to treat malignant tumors. The extract of podophyllum is also widely used as laxative, choleretic, and effective medicine for treating snake venom, psoriasis, gonorrhea, etc. In 1942, Chaplains applied podophyllotoxin locally to treat genital warts and achieved satisfactory results. So far, podophyllotoxin is still the most effective agent for treating genital warts, mainly in the form of ethanol solution of podophyllotoxin and podophyllotoxin ointment.

In 1947, scientists confirmed the destructive effect of podophyllotoxin on animal cancer cells, which led to extensive medical, biological and chemical research. However, because the alcohol solution of podophyllotoxin is unstable, it is difficult to obtain a therapeutic dose. Certainly, coupled with the high toxicity of podophyllotoxin, the use of podophyllotoxin as an anti-tumor drug is greatly restricted. Beginning in the 1950s, many foreign research institutions (including the National Cancer Treatment Center) began to carry out a lot of structural modification work on podophyllotoxin, in order to obtain compounds with less toxic and side effects, but can retain the anti-tumor activity of podophyllotoxin. Researchers at Sandoz Pharmaceutical Company successfully synthesized etoposide (Etoposide, VP-16, 1.2) and teniposide (Teniposide, VM-26, 1.3) in 1966 and 1967, respectively. These two compounds have been shown to be effective against AML (acute myeloid leukemia), Hodgkin's disease, non-Hodgkin's lymphoma, lung cancer (including small cell and non-small cell lung cancer), gastric cancer, breast cancer, and ovarian cancer. VP-16 was approved by the FDA in 1983 and has become one of the most clinically used antineoplastic drugs. However, they still have the following disadvantages: poor water solubility, narrow anti-tumor spectrum, easy inactivation through metabolism, easy formation of drug resistance and severe myelosuppression and other toxic effects, which limit their wide application in clinical practice. It prompts people to further carry out structural modification and pharmacological screening of the podophyllotoxin nucleus, or to find new dosage forms of podophyllotoxin, in order to obtain anticancer drugs with high efficiency and low toxicity.

Contents of the invention

The purpose of the present invention is to provide the application of solid lipid nanoparticles as the carrier of podophyllotoxin and its derivatives and the new drug dosage form of podophyllotoxin.

Utilizing the characteristics of slow release, targeting, stability and safety of solid lipid nanoparticles, it is used as a drug carrier of podophyllotoxin and forms a new drug dosage form for the delivery and targeting of podophyllotoxin and its derivatives. To improve the curative effect of podophyllotoxin and its derivatives, reduce the toxicity and adverse reactions of podophyllotoxin and its derivatives.

One aspect of the present invention provides the application of solid lipid nanoparticles as drug carrier materials for podophyllotoxin and its derivatives. Using solid lipid nanoparticles as a carrier material has good biocompatibility, low toxicity, slow release, targeting, stability, and safety. It can prolong the circulation time of podophyllotoxin in the body, and improve Bioavailability of derivatives.

Another aspect of the present invention also provides a pharmaceutical composition, which contains podophyllotoxin and its derivatives as pharmaceutical active ingredients and solid lipid nanoparticle as a pharmaceutical carrier material.

Further, the mass ratio of the solid lipid nanoparticles to podophyllotoxin is 15-50:1.

The average particle diameter of the solid lipid nanoparticles is 40-80nm.

The above-mentioned solid lipid nanoparticles mainly include carrier materials, emulsifiers and surfactants. Carrier materials include glyceryl esters and fatty acids: glyceryl esters include glyceryl tristearate, glyceryl tripalmitate, glyceryl trimyristate, glyceryl trilaurate and glyceryl tristate, etc.; fatty acids Including stearic acid, palmitic acid and capric acid, etc.; emulsifiers are mainly phospholipids, including lecithin, soybean lecithin and egg yolk phospholipids; surfactants include nonionic surfactants, cholate and short-chain alcohols class etc.

Podophyllotoxin derivatives mainly refer to deglycoside derivatives etoposide (etoposide, VP16, also known as etoposide) and podophylloside (teniposide, VM 26, also known as teniposide) such as 4 methyl epi Podophyllotoxin.

The above pharmaceutical composition may also contain other pharmaceutically acceptable carriers and additives, such as water, glycerin, antioxidants and the like. It can be made into various dosage forms such as solution, tablet, capsule, etc. according to needs, and a film dosage is preferred in the present invention. The administration of the pharmaceutical composition can be through subcutaneous, intradermal, intravenous injection, etc., or through intramuscular injection or delivered to interstitial spaces, or directly delivered to the lesion area.

The present invention also provides a preparation method of podophyllotoxin/podophyllotoxin derivatives-solid lipid nanoparticles, which adopts the modified microemulsion technology-emulsification evaporation-low temperature solidification method, and the process steps are as follows:

(a) dissolving podophyllotoxin/podophyllotoxin derivatives, carrier material and emulsifier in an organic solvent to form an organic phase; dissolving a surfactant in water to form an aqueous phase;

(b) adding the organic phase to the stirred water phase at 70-80°C, and stirring for 4h-6h;

(c) Mix the product in the step (b) with stirred water at 0-2°C, stir for 2h-4h, and the volume of the water is 2-10 times the volume of the solution in the step (b). .

Wherein, the stirring speed of the water phase in steps (b) and (c) is 600-1200 r/min.

The above-mentioned organic solvents are conventional solvents, such as chloroform, acetone, ethanol and the like. The above-mentioned emulsifier is one of lecithin, soybean lecithin and egg yolk phospholipid. The above-mentioned surfactant may be Poloxamer 188 (poloxamer), sodium taurocholate, sodium glycocholate, polyoxyethylene (100) stearate (Myrj59) and the like.

As a drug-loading system for podophyllotoxin and its derivatives, solid lipid nanoparticles have good stability, high encapsulation efficiency, and good release curves, providing an ideal drug-loading system for podophyllotoxin and its derivatives. Way.

In addition, the pharmaceutical composition made by podophyllotoxin and its derivatives and solid lipid nanoparticles has broad application prospects, and the podophyllotoxin and its derivatives solid lipid nanoparticles chitosan film prepared by the present invention have The preparation process is simple, the cost is low, and the process parameters are easy to control; and it has the advantages of good biocompatibility, easy biodegradation, film-forming property, flexibility, etc., and has certain anti-inflammatory and antibacterial effects, which improves the podophyllotoxin and The efficacy of its derivatives. The solid lipid nanoparticles of podophyllotoxin and its derivatives have a slow-release function in the body, which can prolong the circulation time of podophyllotoxin, reduce the toxic and side effects of repeated medication, and improve the bioavailability of podophyllotoxin and its derivatives.

Description of drawings

Figure 1 Transmission electron microscope image of podophyllin solid lipid nanoparticles

Figure 2 Transmission electron microscope image of podophyllin solid lipid nanoparticles

Figure 3 Transmission electron microscope image of solid lipid nanoparticles of podophyllin derivatives

The particle size distribution diagram of Fig. 4 podophyllin solid lipid derivative nanoparticles

Figure 5 Cytotoxicity experiment diagram

The ultraviolet standard curve of Fig. 6 podophyllum aqueous solution

Fig. 7 The cumulative release curve in vitro of podophyllin solid lipid nanoparticles

Figure 8 Tumor cell activity inhibition experiment diagram

Detailed ways

Example 1

Take 100mg of stearic acid and 5ml of acetone and put them into a 25ml stoppered pear-shaped bottle, ultrasonically dissolve them fully, add 100mg of lecithin in chloroform, heat to dissolve, and form an organic phase. Another 300mg of Myrj59 was dissolved in 30ml of high-purity water to form the aqueous phase. Inject the organic phase into the water phase at (75±2)°C stirred at 1000r/min with a 6 ^# needle, and continue to stir for about 4 hours to completely evaporate the organic solvent and concentrate the system to about 5ml, and quickly mix the obtained translucent system in Another 10ml of water phase was stirred at 1000r/min at 0-2°C, and continued to stir for 2h to obtain a blank solid lipid nanoparticle suspension, and the volume of the system was adjusted to 20ml. The obtained blank solid lipid nanoparticle suspension is a stable colloidal dispersion system with uniform appearance, uniform size and uniform distribution, and an average particle diameter of 50.4nm through the measurement of particle size and appearance.

Example 2

Take 10mg of podophyllotoxin, 100mg of stearic acid, and 5ml of acetone, put them into a 25ml stoppered pear-shaped bottle, dissolve them fully by ultrasonication, add 100mg of lecithin in chloroform, heat to dissolve, and form an organic phase. Another 200mg of Myrj59 was dissolved in 30ml of high-purity water to form the water phase. Inject the organic phase into the water phase at (75±2)°C stirred at 1000r/min with a 6 ^# needle, and continue to stir for about 4 hours to completely evaporate the organic solvent and concentrate the system to about 5ml, and quickly mix the obtained translucent system in Another 10ml of the water phase was stirred at 1000r/min at 0-2°C, and continued to stir for 2h to obtain the podophyllin solid lipid nanoparticle suspension, and the system was adjusted to 20ml. Take the podophyllin solid lipid nanoparticle suspension and dilute it with high-purity water, and measure the particle size distribution of the nanoparticle suspension with a laser particle size analyzer; Copper grid covered with carbon film, negatively stained with 2% sodium phosphotungstate solution, let it stand for 15 minutes, observe its particle size and shape under a transmission electron microscope, and obtain the particle size distribution diagram of podophyllin solid lipid nanoparticles And TEM images, see Figures 1, 2, and 4. The obtained podophyllin solid lipid nanoparticle suspension is a uniform and stable colloidal dispersion system in which a slightly bluish-white glossy opalescent band can be seen. The nanoparticles are of uniform size and uniform distribution, with an average particle diameter of 52.9nm.

Example 3

Obtain podophyllotoxin derivative solid lipid nanoparticle suspension with the method in embodiment 2, can find out that gained podophyllotoxin derivative solid lipid nanoparticle size is uniform, uniformly distributed, and average particle size is 54.4nm, see Figure 3.

Example 4

Cytotoxicity was determined by the tetrazolium salt colorimetric method (MTT Assay). The 293T cells were seeded in a 96-well plate at a concentration of 2.5×10 ⁴ cells/well in DMEM (Dulbecco's Modified Eagle Medium) culture medium containing 10% calf serum, and the volume of each well was 100 μl. The MTT (bromide-3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium) used is a product of Sigma Company, and the microplate reader ELX 800uv.

After culturing for 24 hours, the cells adhered to the wall, and 3 wells in each group were added with different concentrations of podophyllotoxin solution, poloxamer188 as a surfactant of podophyllotoxin solid lipid nanoparticle suspension (ghost PSLN) and Mrij59 as a surfactant of podophyllotoxin Phyllotoxin solid lipid nanoparticle suspension (ghost MSLN), concentrations were 10, 20, 30, 40, 50 μg/ml, and blank aqueous solution control, after 24 hours of incubation, 20 μl of MTT solution was added to each well, and discarded after incubation for 4 hours To the supernatant, 150 μl of DMSO was added to each well to terminate the reaction. Shake the culture plate horizontally for 30 minutes, measure the absorbance at 490 nm with an enzyme-linked detector, and calculate the cell survival rate according to the following formula:

Cell viability% = A490 (sample) / A490 (control) × 100%

Wherein A490 (sample) is the cell absorbance after adding the sample, and A490 (control) is the cell absorbance of the blank aqueous solution control.

The experimental results are shown in Figure 5: the cytotoxicity of podophyllotoxin solution, ghost PSLN and ghost MSLN suspension increases with the increase of solution concentration respectively, and the cytotoxicity of ghost PSLN and ghost MSLN is higher than that of podophyllotoxin at the same concentration. The cytotoxicity of the solution is small, which proves that the use of solid lipid nanoparticles as the carrier of podophyllotoxin can reduce the toxicity of podophyllotoxin.

Example 5

The encapsulation efficiency of podophyllin solid lipid nanoparticles was determined by gel column separation method combined with ultraviolet spectrophotometry. First prepare the standard curve, see Figure 5. At a wavelength of 289nm and a concentration range of 5-25 μg/ml, the absorbance of the podophyllum solution has a linear relationship with the concentration, and the regression equation obtained is Abs=10.24203*Conc+0.00323, r=0.9997. Take a certain amount of podophyllin solid lipid nanoparticle suspension and centrifuge it in a high-speed refrigerated centrifuge, put the supernatant on the Sephadex G50 gel column, use high-purity water as the eluent, and take different volumes of elution Part, combined with a UV spectrophotometer to measure the absorbance at 289nm (at this wavelength, the excipients have no absorption interference), calculate the content of free podophyllin in the podophyllin solid lipid nanoparticles according to the standard curve, and calculate the encapsulation efficiency according to the following formula (EE%).

EE%=(W1-W2)/W1×100%

Among them: W1-the total amount of drug; W2-the amount of free drug.

The encapsulation efficiencies of the three batches of podophyllotoxin measured by gel column separation combined with ultraviolet spectrophotometry were 77.50%, 78.90%, and 78.50%, respectively, with an average encapsulation efficiency of 78.30%. The results are shown in Table 1:

Table 1 Podophyllophyllin Solid Lipid Nanoparticle Encapsulation Efficiency Determination Results

W1 (μg/ml) W2(μg/ml) Encapsulation rate (%) Average Encapsulation Efficiency (%) 666625588 150132126 77.50% 78.90% 78.50% 78.30%

The results show that the encapsulation efficiency of solid lipid nanoparticles to podophyllotoxin can reach 78.3%, which is higher than the encapsulation efficiency of podophyllotoxin by conventional carrier materials such as emulsions and nanoparticles, and has reached a higher level.

Example 6

Accurately weigh 5mL podophyllin solid lipid nanoparticle suspension, put it into the treated dialysis bag, and clamp the two ends of the dialysis bag until it does not leak; accurately weigh 50ml of pH7.4 phosphate buffer release solution, put it into into a 100mL beaker; move the drug-filled dialysis bag into a beaker with dissolution medium, keep the sink state, and seal the mouth of the cup; place the beaker in a constant temperature oscillator, set the temperature at (37±1)°C, and the horizontal oscillation frequency at 150 times/min. Take samples at 2, 4, 6, 8, 12, 16, 20, 24, 28, 32 and 36 hours, take out all the dissolution medium in the beaker, and then add 50ml of the same new medium to continue shaking at constant temperature. Measure the concentration of podophyllum in the dissolution medium solution taken out with an ultraviolet spectrophotometer, calculate the release rate of the drug, and make an in vitro drug release curve based on the relationship between the cumulative release rate and time. As shown in Figure 6.

From Fig. 7, it can be observed that at the initial stage of release (2h), there is a burst release phenomenon of the drug (34.5% of the total amount of the drug is released), and then the drug in the SLN is sustained release, and the cumulative release of the drug to 36h is 87.0%. From this result, it can be known that SLN is a skeleton structure of drugs and lipids. Due to the large specific surface area of nanoparticles, part of the drug molecules are adsorbed on the surface of nanoparticles, or enriched in the outer layer of nanoparticles, and the other part is dispersed in the nanoparticle. In the lipid backbone, a solid solution is formed. The drug molecules in the outer layer are released very quickly, resulting in a drug burst phenomenon in the initial stage of the cumulative release curve. Since then, the release of drugs is mainly due to the diffusion from the solid matrix, which is characterized by persistence and slowness. At 36h, the drug was still released from SLN at a relatively constant rate. At this time, the drug released into the release medium still maintains a relatively high stability level, indicating that the drug encapsulated in the carrier is stable.

Example 7

Preparation method of podophyllotoxin solid lipid nanoparticle chitosan film agent

Weigh a certain amount of chitosan, gelatin and corresponding acetic acid solution and mix them with 10ml distilled water in a 50ml beaker, place the beaker in an electric hot water bath at 40°C, and stir the mixture evenly until the chitosan and gelatin are dissolved to form a light yellow gel. Add 5ml of the podophyllotoxin solid lipid nanoparticle suspension prepared in Example 2 into the gel, stir well, take a 10cm×14cm glass plate, and evenly smear the surface with 75% alcohol, and wait until the alcohol is still dry. Lay a layer of polyethylene film, place 15ml of gel on the film and use the salivation method to make a film, dry it in an incubator at 37°C for 12 hours, and then form a film and then sterilize it with ultraviolet rays for 30 minutes.

Example 8

Antitumor activity test of pharmaceutical composition:

EJ (bladder cancer) cells were seeded in a 96-well plate at a concentration of 2.5×10 ⁴ cells/well in RPMI1640 culture medium containing 10% calf serum, with a volume of 100 μl per well. The MTT (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide) used is the product of Sigma Company, and the microplate reader Model 550 Microplate reader.

After culturing the cells for 24 hours to adhere to the wall, add different concentrations of podophyllotoxin solution, podophyllotoxin solid lipid nanoparticle suspension and blank solid lipid nanoparticle suspension (concentrations were 5, 2.5, 1 μg/ml) and Blank and single culture solution control, each sample has 4 multiple wells, after 24h and 48h of culture, add 20μl of MTT solution to each well, discard the supernatant after incubation at 37°C for 4h, add 100μl of DMSO to each well to terminate the reaction. Shake the culture plate horizontally for 30 min, measure the absorbance at 570 nm with an enzyme-linked detector, and calculate the inhibition rate of tumor cell activity.

The experimental results are shown in Figure 8: (where podophyllotoxin 24h/48 refers to podophyllotoxin cultured for 24/48 hours, podophyllo-SLN24h/48 refers to podophyllotoxin solid lipid nanoparticle suspension cultured for 24h/48 hours hours) podophyllotoxin solution and podophyllotoxin solid lipid nanoparticle suspension as the concentration increases, the inhibition rate of tumor cell activity increases correspondingly. When the concentration of podophyllotoxin solution was 5 μg/ml, the inhibition rate was 6.16% in 24h, and reached 48.55% in 48h; the inhibition rate of podophyllotoxin solid lipid nanoparticle suspension was 34.48% in 24h, and could reach 63.83% in 48h, which indicated that Podophyllotoxin solid lipid nanoparticles have slow-release performance and higher inhibition rate, which can improve the drug utilization rate of podophyllotoxin.

Claims (6)

1. a pharmaceutical composition is characterized in that containing active constituents of medicine podophyllotoxin or podophyllotoxin derivative and solid lipid nanoparticle.

2. pharmaceutical composition according to claim 1, the mass ratio that it is characterized in that solid lipid nanoparticle and podophyllotoxin is 15～50: 1.

3. pharmaceutical composition according to claim 1 and 2, the mean diameter that it is characterized in that described solid lipid nanoparticle is 40～80nm.

4. solid lipid nanoparticle is as the application of podophyllotoxin and derivant drug carrier material thereof.

5. the preparation method of podophyllotoxin/podophyllotoxin derivative-solid lipid nanoparticle is characterized in that containing following processing step:

(a) with podophyllotoxin/podophyllotoxin derivative, carrier material and emulsifiers dissolve in organic solvent, constitute organic facies; It is soluble in water to get surfactant, constitutes water;

(b) organic facies is added 70～80 ℃ the water that stirs, stir 4h～6h;

(c) product in the step (b) is mixed in the water of one 0～2 ℃ stirring, stir 2h～4h, the volume of water is 2～10 times of liquor capacity in the step (b).

6. preparation method according to claim 5, it is characterized in that step (b) and (c) in the mixing speed of water be 600～1200r/min.

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